A number of renal cystic diseases (RCD), including Von Hippel-Lindau (VHL), tuberous sclerosis (TSC), polycystic kidney disease (PKD), and acquired cystic disease (AcCD) are characterized by epithelial neoplastic growth, cyst formation and enlargement, and progression to adenoma and various malignancies, including oncocytoma, clear cell carcinoma, and papillary renal cell carcinoma. While the degree varies to which these disorders progress to metastasis, they all have in common 1) cyst formation, 2) neoplastic growth, and 3) tumor formation. VHL, TSC, and PKD are inherited diseases caused by mutation of tumor-suppressor genes (VHL, TSC1, TSC2) or tumor suppressor-like genes (PKD1, PKD2, PKHD1). All have extrarenal pathology as well. Acquired cystic disease is environmental, caused principally by kidney dialysis.
Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a cystic genetic disorder of the kidneys and other organs. It occurs in humans and other animals. PKD is characterized by the presence of multiple cysts (hence, “polycystic”) in both kidneys. The disease can also damage the liver, pancreas, and rarely, the heart and brain vasculature. The two major forms of polycystic kidney disease are distinguished by their patterns of inheritance.
Autosomal dominant polycystic kidney disease (ADPKD) is generally a late-onset disorder characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts. Kidney manifestations in this disorder include renal function abnormalities, hypertension, renal pain, and renal insufficiency. ADPKD is a very common inherited disease, affecting one in 500-1,000 individuals. Two genes give rise to ADPKD in humans—mutations in PKD1 cause ˜85% of ADPKD cases and mutations in PKD2 cause ˜15% of ADPKD cases. In mice, homozygous Pkd1 and Pkd2 null mutations have late-embryo lethal phenotypes and cystic kidneys. The protein products of PKD1 and PKD2 are polycystin-1 (PC1) and polycystin-2 (PC2). A less-common autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in the PKHD1 (polycystic kidney and hepatic disease-1) gene.
Approximately 50% of patients with ADPKD have end-stage renal disease (ESRD) by the age of 60. ADPKD is a systemic disease with cysts in other organs such as the liver (which may lead to cirrhosis), seminal vesicles, pancreas, and arachnoid mater and non-cystic abnormalities such as intracranial aneurysms and dolichoectasias, dilation of the aortic root and dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias. Initial simian and human symptoms are hypertension, fatigue, and mild to severe back or flank pain and urinary tract infections. The disease often leads to chronic renal failure and may result in total loss of kidney function, known as end stage renal disease (ESRD), which requires some form of renal replacement therapy (e.g. dialysis or transplantation).
Autosomal recessive polycystic kidney disease (ARPKD) is much rarer than ADPKD and is often fatal in utero or during the first month of life. The signs and symptoms of the condition are usually apparent at birth or in early infancy.
There is no cure for PKD. The option of a transplant generally only arises after the patient reaches ESRD. Therefore, it would be advantageous to find a therapy to treat, inhibit, and/or prevent PKD of either type.